This application will examine the primary infection of macaques with the SIV strain, SIVsmmPBj14. SIVsmmPBj14 induces severe acute disease, with viremia and high circulating levels of the cytokines tumor necrosis factor alpha (TNFa) and interleukin-6 (IL-6). Experiments proposed will test the hypothesis that immune activation is crucial in the pathogenesis of acute lentiviral disease, through effects on cytokine production, virus replication and apoptosis. In vitro studies will characterize SIVsmmPBj14-induced cellular proliferation. Experiments will test whether cellular proliferation is dependent on endogenous pro- inflammatory cytokines (TNFa, IL-6) or an T cell activation. Studies will also be conducted to assess whether virally-induced T-cell proliferation is dependent on TCR-mediated signaling and/or on specific T-cell costimulatory pathways. In addition, studies will be performed to determine whether SIVsmmPBj14 Nef is required for induction of cellular proliferation and whether sro-homology domains contained within the protein are required for this effect. In vivo experiments will be conducted to directly test whether T cell activation or pro-inflammatory cytokines contribute to acute SIV disease. Finally, the contribution of T-cell activation to the subsequent progression of SIV-induced immunodeficiency will be analyzed directly, using SIVsmmFGB. SIVsmmFGB is closely related to SIVsmmPBj14, but is not acutely lethal--rather, it induces fatal immunodeficiency within 4-6 months. Studies will be conducted to assess the effect that treatment of macaques with cyclosporin-A during the acute-phase of SIVsmmFGB infection has on clinical, immunologic and virologic parameters.